Trial Review

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International Breast cancer Intervention Study (IBIS-II) Bone Sub-Protocol, A randomised double-blind trial to assess the effects on bone mineral density and bone biomarkers of anastrozole when used to prevent breast cancer in postmenopausal women

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Secondary ID [1]1220

National Clinical Trials Registry: NCTR583

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Universal Trial Number (UTN)

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Trial acronym

ANZ 02P2/IBIS II (Bone)

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Linked study record

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Health condition

Health condition(s) or problem(s) studied:

Increased breast cancer risk3050

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Osteoporosis3060

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Osteopenia3070

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Bone fractures3080

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Condition category

Condition code

Cancer34834800

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Breast

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Musculoskeletal34934900

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Osteoporosis

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Other35035000

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Fractures

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Intervention/exposure

Study type

Interventional

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Description of intervention(s) / exposure

The purpose of the bone sub-study is to examine the effect of anastrozole on Bone Mineral Density (BMD) and the risk of developing osteoporosis and fractures. Additionally it will explore the ability of bisphosphonate treatment to reduce the risk in women found to have low bone mineral density at baseline. BMD measurements in the lumbar spine and femoral neck will be performed in 1000 women from the initial entrants of the 6,000 women enrolled in the IBIS-II Prevention Trial (IBIS-II Prevention Protocol). The women will be divided into the following three strata: I. 300 women with T-scores (T) greater than or equal to minus one. These women will be monitored with dual energy X-ray absorptiometry (DXA) scans and recommended to take vitamin D and calcium supplements, but will not initially receive risedronate; II. 400 moderately to severely osteopenic women with T-scores between minus one and minus two point five will be randomised between risedronate sodium (Actonel, 35 mg, orally, once per week) or placebo (lactose pill, orally, once per week) and monitored by DXA scans. Vitamin D and calcium tablets will be recommended to all women; III. 300 Osteoporotic women with T-scores between minus two point five and minus four or up to two low trauma vertebral fractures will be required to take risedronate and be monitored by DXA scans. Risedronate is the bisphosphonate which will be used in the sub-study. The dose is 35 mg oral once a week and treatment will continue for 5 years.

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Intervention code [1]2410

Prevention

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Comparator / control treatment

Placebo

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Control group

Placebo

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Outcomes

Primary outcome [1]4030

To quantify the changes in bone in the spine and femur in postmenopausal women treated with anastrozole compared with the placebo group.

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Timepoint [1]4030

The primary comparison of Anastrozole compared to Placebo will occur at 3 years. Data for use in this comparison and any subsequent comparisons which may be undertaken will be recorded at baseline, and at the 1, 3, 5 and 7 year visits.

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Primary outcome [2]4040

To evaluate the impact of bisphosphonate treatment on bone mineral density and bone metabolism in women taking anastrozole, and who are found to be osteoporotic or moderate to severely osteopenic at baseline. Bisphosphonate treatment will be required for women who are found to be osteoporotic at baseline, and will be a randomised option in women who are moderate to severely osteopenic at baseline.

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Timepoint [2]4040

The primary comparison of Anastrozole compared to Placebo will occur at 3 years.Data for use in this comparison and any subsequent comparisons which may be undertaken will be recorded at baseline, and at the 1, 3, 5 and 7 year visits.

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Primary outcome [3]4050

To explore the relationship between changes in levels of biochemical markers of bone metabolism with longer term changes in bone mineral density as measured by DXA, related to bone metabolism.

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Timepoint [3]4050

BMD results at the lumbar spine, total hip and femoral neck sites for the 1, 3, 5 and 7-year follow-up visits will be expressed as the percentage change from baseline and analysed using one-way ANOVA after taking logarithms. Statistical significance of the differences between anastrozole and placebo for the ratio of baseline to follow-up sample (1,3,5 and 7) will be analysed using the Wilcoxon Ranksum Test. Evaluations will be undertaken at each of the follow-up times, but the primary analysis will be based on the 3 year follow-up samples. Statistical significance will be assessed based on a 2-sided p-value of less than 0.05. In addition, a further analysis will be performed on the 7-year data based on the percentage change in BMD from the end of trial medication at Year 5.

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Secondary outcome [1]8750

Not Applicable

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Timepoint [1]8750

Not applicable

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Eligibility

Key inclusion criteria

Women meeting the entry criteria of the IBIS-II (Prevention) trial will be offered entry into the bone sub-protocol. Women will be selected from the first women randomised into the main trial, and will be enrolled for the sub-protocol subject to: (1) giving informed consent; (2) not being excluded by one or more of the exclusion criteria listed below. Women with T-scores < -2.5 and > -4.0 or 1-2 low trauma vertebral fractures must be treated with risedronate.

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Minimum age

40Years

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Maximum age

70Years

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Gender

Females

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Can healthy volunteers participate?

No

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Key exclusion criteria

criteria: 1. Women with previous bilateral hip fractures or bilateral hip prostheses. This is because reliable DXA scans cannot be performed.2. Women currently with any type of metabolic bone disease including: Paget's disease, osteogenesis imperfecta, disorders of calcium or mineral metabolism, renal calculus, malabsorption, hyper- or hypocalcaemia, hyper- or hypoparathyroidism, hyper- or hypothyroidism (NB: women on stable thyroid replacement therapy can be included provided they are euthyroid as judged by the investigator). Women with previous conditions that have been corrected are eligible.3. Women who have regularly taken any medication affecting bone metabolism within the past 12 months including oestrogen, any bisphosphonate, parathyroid hormone, calcitonin, oral or systemic glucocorticoid.However, women who have been diagnosed as osteoporotic and are currently taking oral bisphosphonate can join stratum III of the bone sub-study providing their T-score is <-2.5 at the time of randomisation (DXA scan done within 3 months of joining the study).4. Women who have a T score less than -4 and/or more than 2 low trauma vertebral fractures.

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Study design

Purpose of the study

Prevention

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Allocation to intervention

Randomised controlled trial

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Procedure for enrolling a subject and allocating the treatment (allocation concealment
procedures)

The ANZ BCTG Statistical Centre at the NHMRC Clinical Trials Centre will provide a central fax randomisation service for all Australian and New Zealand institutions. For stratum II only, at the time of study entry the participants will be allocated a treatment code and study drug will be supplied in accordance with the treatment code.

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Methods used to generate the sequence in which subjects will be randomised (sequence
generation)

This sub-study is assessing the effects of the drug anastrozole on bone mineral density and other indicators on bone strength, when this drug is used to prevent breast cancer in postmenopausal women.This is an ANZ02P2/International Breast cancer Intervention Study: IBIS II Bone Sub-Protocol.

Who is it for?You can join this trial if:You are joining the ANZ02P2 International Breast cancer Intervention Study: IBIS II (Prevention).You must not have not previously have had bilateral hip fractures or bilateral hip prostheses. You must not have a metabolic bone disease. You can not have regularly taken any medication affecting bone metabolism within the past 12 months unless you have been diagnosed as osteoporotic and are currently taking oral bisphosphonate (a bone strengthening drug).

Trial detailsParticipants will be divided into three groups based on the results of their baseline bone mineral density scans. Group 1 will comprise of participants with normal bone density. It will be recommended that these participants take calcium and vitamin D supplements. Group 2 will comprise of participants with osteopaenia (or reduced bone mineral density). These participants will be divided into two groups. One group will take the drug risedronate orally once a week for 5 years while the other group takes an inactive compound. It will be recommended that these participants also take calcium and vitamin D supplements. Group 3 consists of participants diagnosed with osteoporosis (low bone mineral density). These participants will take risedronate orally once a week for 5 years. All women in this sub-study (Groups 1, 2 and 3) will be monitored with bone mineral density scans.

Risedronate is a type of drug called a bisphosphonate which acts to increase bone mass and strength.